The first hyaluronan gel was prepared by Pharmacia AB (Uppsala, Sweden) in the early 1960s (36) by using 1,2,3,4-diepoxybutane as a cross-linking agent. This chemical has been widely used for cross-linking of polysaccharides such as cellulose and dextran. The epoxy cross-linked hyaluronan was prepared to be used for column chromatography and not for therapeutic use because of its poor biocompatibility. Water-insoluble hyaluronan gels for various therapeutic uses were first synthesized in the 1980s by creating sulfonyl-bis-ethyl cross-links between the polysaccharide chains (37-40). The gel was found to be highly biocompatible, which means it did not elicit allergic, inflammatory, granulation or foreign body reactions (41-43). Because the gel can be made at a very low polymer concentration ($ 0.1%) with sufficient solidity and very high elasticity, it is ideal as tissue filler or artificial intercellular matrix. Its high water content (> 99%) makes it very permeable to small metabolites, and therefore it does not create a metabolic barrier between cells (44,45). Furthermore it is very stable when injected as gel slurry through a very narrow needle (30 gauge) into connective tissues or implanted as a slab of hydrated gel or as a dry membrane that rehydrates in the tissue (46). When the hyaluronan is injected as gel slurry, cells can grow in between the particles. When it is implanted as a larger piece of gel as a slab or membrane, cells will not degrade it, but they can attach to these surfaces. The half-life tissue of C14-labeled hylan B gel in guinea pig dermis was found to be approximately 12 months (45,47). The very elastic gel particles (0.1-1 mm diameter) deform during the injection and then regain their original form in the tissue. Because the soft particles are not round but polygonal, forces produced by muscle movements and massage of the tissues will cause their fragmentation into very small pieces, which eventually migrate from the site of injection (45,47).
Another important biological property of hylan B gel is its remarkable hemocompatibility (48,49). Thrombocytes and proteins that participate in blood coagulation do not interact with this gel. Hyaluronan in the native form is also extremely compatible with blood, and therefore it is important that the chemical and structural changes introduced by the cross-linking process do not diminish this compatibility (48,49).
Tissue engineering with viscoelastic hyaluronan focused first on its use as a tissue filler or tissue augmentator (viscoaugmentation). Unlike collagen and non-biological tissue fillers, hyaluronan is an extremely elastic molecule and as such provides elasticity to the intercellular spaces into which it is injected. Hylan B gel was first used for viscoaugmentation of the vitreus after retinal detachment surgery, and later for correcting facial wrinkles and depressed scars for vocal cord augmentation in glottal insufficiency and augmentation of the connective tissue in sphincter muscles to treat urinary incontinence.
The second hyaluronan gel to be used for viscoaugmentation was made by using various epoxy compounds (50-53). Because the cross-linking was light, the products—liquid or gels—became biocompatible. Most of the gels used contained more polymer $ 2%) than hylan B gel (# 0.5%) and consequently they became more solid and less elastic (44). To differentiate this hyaluronan from hylan B gel the developers called it 'stabilized hyaluronan' (54). The rheological properties of these gels have been described recently (55). Despite the considerable differences in the chemical composition and rheological properties of these two gels, their utility in medical therapeutics and medical cosmetics is comparable.
Other cross-linked gels of hyaluronan have been developed in the recent years. The most important requirements of these gels are their biodegradability and biocompatibility. Depending on the intended use, gels that slowly dissolve in the biological environment or those that do not dissolve at all are preferred. Very few of these gels have been tested in clinical experiments.
Hyaluronan cross-linked with ferric ions forms a viscous solution or gel depending on the concentration of the polymer and the cation (Gynecare Intergel®, Lifecore Biomedical Inc., Chaska, MN). Animal studies and clinical trials indicated that this absorbable preparation can be used intraperitoneally after open conservative gynecological surgery to reduce post-surgical adhesions (56).
Slowly soluble (biodegradable) and insoluble hyaluronan gels were produced by ester or ether linkages and tested in vitro and in animal studies (57-61).
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